Oxygen is essential to many physiological and metabolic processes, including aerobic metabolism. A lack of oxygen for implanted cells often leads to cell injury or death. Oxygen provision is a vital component in sustaining transplanted cells.
The success of many transplants is compromised not only due to graft-host rejections, but also by ischemic conditions generated by insufficient oxygen supply to the transplant. Following implantation of the cells, oxygen can be provided to the implanted cells from the body tissue (mainly via diffusion). However, the natural diffusion rate is too low in order to provide the cells with a significant, necessary amount of oxygen amount.
Islet transplantation in experimental models is conducted under the influence of immunosuppressive drugs. Such immunosuppression is typically associated with adverse effects such as increased infection and malignancy rates. Additionally, the immunosuppressive drugs are known to affect the viability and the functionality of the transplanted islets and to trigger insulin resistance in the animal model.
Islets have been microencapsulated in various polymeric hydrogel matrices including alginate, acrylic acid derivatives, polyethylene glycol (PEG) conformal micro-coatings, nanocoatings, cellulose, and/or agarose. Microencapsulated islets are typically transplanted within the peritoneal space, but have also been implanted within the liver, the spleen, and the subcapsular space of the kidney. Microencapsulating islets provides a low ratio (typically about 1:100) of (a) the volume of islets to (b) the volume of alginate hydrogel (i.e., capsule). The subcapsular space of the kidney cannot sufficiently support the relatively large volume of alginate microcapsules.
U.S. Pat. No. 6,165,225 to Antanavich et al. describes bioartificial implants and methods for their manufacture and use, particularly bioartificial pancreases. In particular, the implants may be thin sheets which enclose cells, may be completely biocompatible over extended periods of time and may not induce fibrosis. The high-density-cell-containing thin sheets are preferably completely retrievable, and have dimensions allowing maintenance of optimal tissue viability through rapid diffusion of nutrients and oxygen and also allowing rapid changes in the secretion rate of insulin and/or other bioactive agents in response to changing physiology. Implantations of living cells, tissue, drugs, medicines and/or enzymes, contained in the bioartificial implants may be made to treat and/or prevent disease.
PCT Publication WO 07/144389 to Durfane et al. describes cellular devices comprising a collagen matrix, cell layer, and gelled alginate layer, processes for producing the devices, methods of implanting the devices, and methods of treatment thereof.
In a conference report entitled, “Bioartificial Organs II: Conference Report,” co-sponsored by The Engineering Foundation and the Juvenile Diabetes Foundation International, from a conference held in Banff, Alberta, Canada, Jul. 18-22, 1998, the portion relating to a bioartificial pancreas described the use of “medium-sized capsules” of 350 μm. This would correspond to a transplant volume of 35 mL for a 70 kg individual. A five-month diabetes reversal in dogs was observed in transplantation of the capsules in the peritoneum or omental pouch.
U.S. Pat. No. 6,960,351 to Dionne describes an immunoisolatory vehicle for the implantation into an individual of cells which produce a needed product or provide a needed metabolic function. The vehicle is comprised of a core region containing isolated cells and materials sufficient to maintain the cells, and a permselective, biocompatible, peripheral region free of the isolated cells, which immunoisolates the core yet provides for the delivery of the secreted product or metabolic function to the individual. The vehicle is described as being particularly well-suited to delivery of insulin from immunoisolated islets of Langerhans, and can also be used for delivery of high molecular weight products, such as products larger than IgG. A method of making a biocompatible, immunoisolatory implantable vehicle is described, consisting in a first embodiment of a coextrusion process, and in a second embodiment of a stepwise process. A method is also described for isolating cells within a biocompatible, immunoisolatory implantable vehicle, which protects the isolated cells from attack by the immune system of an individual in whom the vehicle is implanted. A method is provided for providing a needed biological product or metabolic function to an individual, comprising implanting into the individual an immunoisolatory vehicle containing isolated cells which produce the product or provide the metabolic function.
PCT Publication WO 01/50983 to Vardi et al., and U.S. patent application Ser. No. 10/466,069 in the national phase thereof, which are assigned to the assignee of the present application and are incorporated herein by reference, describe an implantable device comprising a chamber for holding functional cells and an oxygen generator for providing oxygen to the functional cells. In one embodiment, the oxygen generator is described as comprising photosynthetic cells that convert carbon dioxide to oxygen when illuminated. In another embodiment, the oxygen generator is described as comprising electrodes that produce oxygen by electrolysis.
Stabler C et al., in an article entitled, “The effects of alginate composition on encapsulated βTC3 cells,” (Biomaterials vol. 22, no 11, pp. 1301-1310 (2001)), describe the effects of alginate composition on the growth of murine insulinoma βTC3 cells encapsulated in alginate/poly-L-lysine/alginate (APA) beads, and on the overall metabolic and secretory characteristics of the encapsulated cell system for four different types of alginate. Two of the alginates used had a high guluronic acid content (73% in guluronic acid residues) with varying molecular weight, while the other two had a high mannuronic acid content (68% in mannuronic acid residues) with varying molecular weight. Each composition was tested using two different polymer concentrations. Their data show that βTC3 cells encapsulated in alginates with a high guluronic acid content experienced a transient hindrance in their metabolic and secretory activity because of growth inhibition. Conversely, βTC3 cells encapsulated in alginates with a high mannuronic acid content experienced a rapid increase in metabolic and secretory activity as a result of rapid cell growth. Their data also demonstrate that an increase in either molecular weight or concentration of high mannuronic acid alginates did not alter the behavior of the encapsulated βTC3 cells. Conversely, an increase in molecular weight and concentration of high guluronic acid alginates prolonged the hindrance of glucose metabolism, insulin secretion and cell growth. These observations were interpreted as resulting from changes in the microstructure of the alginate matrix, i.e., interaction between the contiguous guluronic acid residues and the Ca2 ions, as a result of the different compositions.
Cheng S Y et al., in an article entitled, “Insulin secretion dynamics of free and alginate-encapsulated insulinoma cells,” (Cytotechnology 51:159-170 (2006)), describe the effect of alginate/poly-1-lysine/alginate (APA) encapsulation on the insulin secretion dynamics exhibited by an encapsulated cell system. Experiments were performed with the aid of a home-built perfusion apparatus providing 1 min temporal resolution. Insulin profiles were measured from: (i) murine insulinoma βTC3 cells encapsulated in calcium alginate/poly-1-lysine/alginate (APA) beads generated with high guluronic (G) or high mannuoric (M) content alginate, and (ii) murine insulinoma βTC-tet cells encapsulated in high M APA beads and propagated in the presence and absence of tetracycline. Results show that encapsulation in APA beads did not affect the insulin secretion profile shortly post-encapsulation. However, remodeling of the beads due to cell proliferation affected the insulin secretion profiles; and inhibiting remodeling by suppressing cell growth preserved the secretion profile. The implications of these findings regarding the in vivo function of encapsulated insulin secreting cells are discussed.
PCT Publication WO 86/03781 to Larsen et al. describes a process for producing alginates having improved physical properties, by the inoculation of alginates derived from brown algae or bacteria, with an enzyme preparation such as a mannuronan-C-5-epimerase preparation from Azotobacter vinelandii. The modified alginates are used for immobilizing enzymes, cell organelles or cells as well as for the microencapsulation of biocatalysts.
PCT Publication WO 02/024107 to Dorain et al. describes a method for making a physiologically active and biocompatible cellular implant for implantation into a host body. The method includes the steps of: (a) forming first and second layers of first and second polymer solutions, respectively, each layer having a first substantially uncross-linked surface and an opposing second cross-linked surface; (b) forming a sandwich of a cell suspension layer of physiologically active cells in a substantially uncross-linked third solution between the first and second, and (c) cross-linking the first and second polymer solutions in a direction toward the cell suspension layer, thereby forming a cellular implant. In another embodiment, all polymer solutions initially are uncross-linked and sequentially spread in layers followed by cross-linking.
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